Atrial Arrhythmias in Astronauts - Summary of a NASA Summit

Background and Problem Definition: To evaluate NASA s current standards and practices related to atrial arrhythmias in astronauts, Space Medicine s Advanced Projects Section at the Johnson Space Center was tasked with organizing a summit to discuss the approach to atrial arrhythmias in the astronaut cohort. Since 1959, 11 cases of atrial fibrillation, atrial flutter, or supraventricular tachycardia have been recorded among active corps crewmembers. Most of the cases were paroxysmal, although a few were sustained. While most of the affected crewmembers were asymptomatic, those slated for long-duration space flight underwent radiofrequency ablation treatment to prevent further episodes of the arrhythmia. The summit was convened to solicit expert opinion on screening, diagnosis, and treatment options, to identify gaps in knowledge, and to propose relevant research initiatives. Summit Meeting Objectives: The Atrial Arrhythmia Summit brought together a panel of six cardiologists, including nationally and internationally renowned leaders in cardiac electrophysiology, exercise physiology, and space flight cardiovascular physiology. The primary objectives of the summit discussions were to evaluate cases of atrial arrhythmia in the astronaut population, to understand the factors that may predispose an individual to this condition, to understand NASA s current capabilities for screening, diagnosis, and treatment, to discuss the risks associated with treatment of crewmembers assigned to long-duration missions or extravehicular activities, and to discuss recommendations for prevention or management of future cases. Summary of Recommendations: The summit panel s recommendations were grouped into seven categories: Epidemiology, Screening, Standards and Selection, Treatment of Atrial Fibrillation Manifesting Preflight, Atrial Fibrillation during Flight, Prevention of Atrial Fibrillation, and Future Researc

Design of lipid nanoparticle delivery agents for multivalent display of recombinant Env trimers in HIV vaccination

Background: Immunization strategies that elicit antibodies capable of neutralizing diverse strains of the virus will likely be an important part of a successful vaccine against HIV. The envelope trimer is the only neutralizing target on the virus, and strategies to promote durable, high avidity antibody responses against the native intact trimer structure are lacking. We recently developed chemically-crosslinked lipid nanocapsules as carriers of molecular adjuvants and encapsulated or surface-displayed antigens, which promote follicular helper T-cell responses and elicited high-avidity, durable antibody responses to a candidate malaria antigen (Moon et al. Nat. Mater. 10 243 (2011); Moon et al. PNAS 109 1080 (2012)). Methods: To apply this system to the delivery of HIV antigens, we developed a strategy to anchor recombinant envelope trimers to the surfaces of these particles under conditions preserving the antigenic integrity of the trimers, allowing multivalent display of these immunogens for immunization. To anchor trimers in their native orientation, gp140 trimers with terminal his-tags were anchored to the surface of lipid nanocapsules via Ni-NTA-functionalized lipids. Results: Owing to their significant size (409 kDa) and heavy glycosylation, we found that liquid-ordered and/or gel-phase lipid compositions were required to stably anchor trimers to particle membranes. Trimer-loaded nanocapsules carrying monophosphoryl lipid A elicited durable antibody responses with titers comparable to a Complete Freund’s Adjuvant (CFA)-like emulsion in mice, without the toxic inflammation associated with the latter adjuvant. Further, nanocapsules elicited strong helper T-cell responses associated with a steadily increasing avidity of trimer-binding antibody over 90 days, which was not replicated by other adjuvants. Conclusion: These results suggest that nanoparticles displaying HIV trimers in an oriented, multivalent presentation can promote key aspects of the humoral response against Env immunogens.National Institutes of Health (U.S.) (AI095109)Massachusetts Institute of Technology. Ragon Institute of MGH, MIT, and Harvar

Atrial Arrhythmias in Astronauts. Summary of a NASA Summit

This slide presentation reviews the findings of a panel of heart experts brought together to study if atrial arrhythmias more prevalent in astronauts, and potential risk factors that may predispose astronauts to atrial arrhythmias. The objective of the panel was to solicit expert opinion on screening, diagnosis, and treatment options, identify gaps in knowledge, and propose relevant research initiatives. While Atrial Arrhythmias occur in approximately the same percents in astronauts as in the general population, they seem to occur at younger ages in astronauts. Several reasons for this predisposition were given: gender, hypertension, endurance training, and triggering events. Potential Space Flight-Related Risk factors that may play a role in precipitating lone atrial fibrillation were reviewed. There appears to be no evidence that any variable of the space flight environment increases the likelihood of developing atrial arrhythmias during space flight

A Comparative Study of the ReCell® Device and Autologous Spit-Thickness Meshed Skin Graft in the Treatment of Acute Burn Injuries.

Early excision and autografting are standard care for deeper burns. However, donor sites are a source of significant morbidity. To address this, the ReCell® Autologous Cell Harvesting Device (ReCell) was designed for use at the point-of-care to prepare a noncultured, autologous skin cell suspension (ASCS) capable of epidermal regeneration using minimal donor skin. A prospective study was conducted to evaluate the clinical performance of ReCell vs meshed split-thickness skin grafts (STSG, Control) for the treatment of deep partial-thickness burns. Effectiveness measures were assessed to 1 year for both ASCS and Control treatment sites and donor sites, including the incidence of healing, scarring, and pain. At 4 weeks, 98% of the ASCS-treated sites were healed compared with 100% of the Controls. Pain and assessments of scarring at the treatment sites were reported to be similar between groups. Significant differences were observed between ReCell and Control donor sites. The mean ReCell donor area was approximately 40 times smaller than that of the Control (P < .0001), and after 1 week, significantly more ReCell donor sites were healed than Controls (P = .04). Over the first 16 weeks, patients reported significantly less pain at the ReCell donor sites compared with Controls (P ≤ .05 at each time point). Long-term patients reported higher satisfaction with ReCell donor site outcomes compared with the Controls. This study provides evidence that the treatment of deep partial-thickness burns with ASCS results in comparable healing, with significantly reduced donor site size and pain and improved appearance relative to STSG

Characterization of a Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as a Risk Factor for Disorders of Sex Development and Reproduction

Disorders of sex development (DSD) and reproduction are not uncommon among horses, though knowledge about their molecular causes is sparse. Here we characterized a 200 kb homozygous deletion in chromosome 29 at 29.7-29.9 Mb. The region contains AKR1C genes which function as ketosteroid reductases in steroid hormone biosynthesis, including androgens and estrogens. Mutations in AKR1C genes are associated with human DSDs. Deletion boundaries, sequence properties and gene content were studied by PCR and whole genome sequencing of select deletion homozygotes and control animals. Deletion analysis by PCR in 940 horses, including 622 with DSDs and reproductive problems and 318 phenotypically normal controls, detected 67 deletion homozygotes of which 79% were developmentally or reproductively abnormal. Altogether, 8-9% of all abnormal horses were homozygous for the deletion, with the highest incidence (9.4%) among cryptorchids. The deletion was found in 4% of our phenotypically normal cohort, 1% of global warmblood horses and ponies, and 7% of draught breeds of general horse population as retrieved from published data. Based on the abnormal phenotype of the carriers, the functionally relevant gene content, and the low incidence in general population, we consider the deletion in chromosome 29 as a risk factor for equine DSDs and reproductive disorders

TGF-beta 1 induces human alveolar epithelial to mesenchymal cell transition (EMT)

Background: Fibroblastic foci are characteristic features in lung parenchyma of patients with idiopathic pulmonary fibrosis (IPF). They comprise aggregates of mesenchymal cells which underlie sites of unresolved epithelial injury and are associated with progression of fibrosis. However, the cellular origins of these mesenchymal phenotypes remain unclear. We examined whether the potent fibrogenic cytokine TGF-β1 could induce epithelial mesenchymal transition (EMT) in the human alveolar epithelial cell line, A549, and investigated the signaling pathway of TGF-β1-mediated EMT. Methods: A549 cells were examined for evidence of EMT after treatment with TGF-β1. EMT was assessed by: morphology under phase-contrast microscopy; Western analysis of cell lysates for expression of mesenchymal phenotypic markers including fibronectin EDA (Fn-EDA), and expression of epithelial phenotypic markers including E-cadherin (E-cad). Markers of fibrogenesis, including collagens and connective tissue growth factor (CTGF) were also evaluated by measuring mRNA level using RT-PCR, and protein by immunofluorescence or Western blotting. Signaling pathways for EMT were characterized by Western analysis of cell lysates using monoclonal antibodies to detect phosphorylated Erk1/2 and Smad2 after TGF-β1 treatment in the presence or absence of MEK inhibitors. The role of Smad2 in TGF-β1-mediated EMT was investigated using siRNA. Results: The data showed that TGF-β1, but not TNF-α or IL-1β, induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT in a time-and concentration-dependent manner. The process of EMT was accompanied by morphological alteration and expression of the fibroblast phenotypic markers Fn-EDA and vimentin, concomitant with a downregulation of the epithelial phenotype marker E-cad. Furthermore, cells that had undergone EMT showed enhanced expression of markers of fibrogenesis including collagens type I and III and CTGF. MMP-2 expression was also evidenced. TGF-β1-induced EMT occurred through phosphorylation of Smad2 and was inhibited by Smad2 gene silencing; MEK inhibitors failed to attenuate either EMT-associated Smad2 phosphorylation or the observed phenotypic changes. Conclusion: Our study shows that TGF-β1 induces A549 alveolar epithelial cells to undergo EMT via Smad2 activation. Our data support the concept of EMT in lung epithelial cells, and suggest the need for further studies to investigate the phenomenon

Time and event-specific deep learning for personalized risk assessment after cardiac perfusion imaging

Standard clinical interpretation of myocardial perfusion imaging (MPI) has proven prognostic value for predicting major adverse cardiovascular events (MACE). However, personalizing predictions to a specific event type and time interval is more challenging. We demonstrate an explainable deep learning model that predicts the time-specific risk separately for all-cause death, acute coronary syndrome (ACS), and revascularization directly from MPI and 15 clinical features. We train and test the model internally using 10-fold hold-out cross-validation (n = 20,418) and externally validate it in three separate sites (n = 13,988) with MACE follow-ups for a median of 3.1 years (interquartile range [IQR]: 1.6, 3.6). We evaluate the model using the cumulative dynamic area under receiver operating curve (cAUC). The best model performance in the external cohort is observed for short-term prediction - in the first six months after the scan, mean cAUC for ACS and all-cause death reaches 0.76 (95% confidence interval [CI]: 0.75, 0.77) and 0.78 (95% CI: 0.78, 0.79), respectively. The model outperforms conventional perfusion abnormality measures at all time points for the prediction of death in both internal and external validations, with improvement increasing gradually over time. Individualized patient explanations are visualized using waterfall plots, which highlight the contribution degree and direction for each feature. This approach allows the derivation of individual event probability as a function of time as well as patient- and event-specific risk explanations that may help draw attention to modifiable risk factors. Such a method could help present post-scan risk assessments to the patient and foster shared decision-making

Artificial gravity partially protects space-induced neurological deficits in Drosophila melanogaster

Spaceflight poses risks to the central nervous system (CNS), and understanding neurological responses is important for future missions. We report CNS changes in Drosophila aboard the International Space Station in response to spaceflight microgravity (SFμg) and artificially simulated Earth gravity (SF1g) via inflight centrifugation as a countermeasure. While inflight behavioral analyses of SFμg exhibit increased activity, postflight analysis displays significant climbing defects, highlighting the sensitivity of behavior to altered gravity. Multi-omics analysis shows alterations in metabolic, oxidative stress and synaptic transmission pathways in both SFμg and SF1g; however, neurological changes immediately postflight, including neuronal loss, glial cell count alterations, oxidative damage, and apoptosis, are seen only in SFμg. Additionally, progressive neuronal loss and a glial phenotype in SF1g and SFμg brains, with pronounced phenotypes in SFμg, are seen upon acclimation to Earth conditions. Overall, our results indicate that artificial gravity partially protects the CNS from the adverse effects of spaceflight

Automatic Hip Fracture Identification and Functional Subclassification with Deep Learning

Purpose: Hip fractures are a common cause of morbidity and mortality. Automatic identification and classification of hip fractures using deep learning may improve outcomes by reducing diagnostic errors and decreasing time to operation. Methods: Hip and pelvic radiographs from 1118 studies were reviewed and 3034 hips were labeled via bounding boxes and classified as normal, displaced femoral neck fracture, nondisplaced femoral neck fracture, intertrochanteric fracture, previous ORIF, or previous arthroplasty. A deep learning-based object detection model was trained to automate the placement of the bounding boxes. A Densely Connected Convolutional Neural Network (DenseNet) was trained on a subset of the bounding box images, and its performance evaluated on a held out test set and by comparison on a 100-image subset to two groups of human observers: fellowship-trained radiologists and orthopaedists, and senior residents in emergency medicine, radiology, and orthopaedics. Results: The binary accuracy for fracture of our model was 93.8% (95% CI, 91.3-95.8%), with sensitivity of 92.7% (95% CI, 88.7-95.6%), and specificity 95.0% (95% CI, 91.5-97.3%). Multiclass classification accuracy was 90.4% (95% CI, 87.4-92.9%). When compared to human observers, our model achieved at least expert-level classification under all conditions. Additionally, when the model was used as an aid, human performance improved, with aided resident performance approximating unaided fellowship-trained expert performance. Conclusions: Our deep learning model identified and classified hip fractures with at least expert-level accuracy, and when used as an aid improved human performance, with aided resident performance approximating that of unaided fellowship-trained attendings.Comment: Presented at Orthopaedic Research Society, Austin, TX, Feb 2, 2019, currently in submission for publicatio

Disparities in Non-invasive Traditional and Advanced Testing for Coronary Artery Disease: Findings from the INCAPS-COVID 2 Study

The COVID-19 pandemic disrupted delivery of cardiovascular care including non-invasive testing protocols and test selection for evaluation of coronary artery disease (CAD). Trends in test selection among traditional versus advanced noninvasive tests for CAD during the pandemic and among countries of varying income status have not been well studied. The International Atomic Energy Agency conducted a global survey to assess pandemic-related changes in the practice of cardiovascular diagnostic testing. Site procedural volumes for noninvasive tests to evaluate CAD from March 2019 (pre-pandemic), April 2020 (onset), and April 2021 (initial recovery) were collected. We considered traditional testing modalities exercise electrocardiography (ECG), stress echocardiography, and stress single-photon emission computed tomography (SPECT), and advanced testing modalities stress cardiac magnetic resonance (CMR), coronary computed tomography angiography (CCTA), and stress positron emission tomography (PET). Survey data were obtained from 669 centers in 107 countries, reporting the performance of 367,933 studies for CAD during the study period. Compared to 2019, traditional tests were performed 14% less frequently (recovery rate 82%) in 2021 versus advanced tests which were performed 15% more frequently (128% recovery rate). CCTA, stress CMR and stress PET showed 14%, 25%, and 25% increases in volumes from 2019 to 2021, respectively. The increase in advanced testing was isolated to high- and upper-middle-income countries, with 132% recovery in advanced tests by 2021 as compared to 55% in lower-income nations. The COVID-19 pandemic exacerbated economic disparities in CAD testing practice between wealthy and poorer countries. Greater recovery rates and even new growth was observed for advanced imaging modalities but this growth was restricted to wealthy countries. Efforts to reduce practice variations in CAD testing due to economic status are warranted.<br/